The overall objectives of this research are to acquire further knowledge of antibody structure and diversity through correlative immunochemical, biochemical, physicochemical, genetic and functional properties of the homogeneous immunoglobulins found in patients with multiple myeloma and related B-cell malignancies. Studies of the monoclonal immunoglobulin components in these and other patients with neoplastic and inflammatory diseases are continuing. The preferential association of the Vlambda VI and Vkappa III subgroups of human light chains with amyloidosis AL(lambda) and with IgM kappa anti-IgG and anti-low-density lipoproteins (LDL) autoantibodies, respectively, was made evident through our immunochemical studies. An antiserum prepared against a lambda Bence Jones protein from a patient who had multiple myeloma and amyloidosis has specificity for lambda light chains of the chemically defined variable (V) region lambda chain subgroup lambda VI. Sequence analyses of this and five other lambda light chains (also obtained from patients with amyloidosis AL) recognized immunologically as the Vlambda VI subgroup revealed that all six proteins had the N-terminal sequence characteristic for prototype lambda VI proteins. The isotypic nature of the Vlambda VI subgroup was demonstrated, and its frequency was estimated to be approximately 5%. However, we found that 5 of 42 lambda-type monoclonal immunoglobulins from patients with amyloidosis AL contained lambda VI-type light chains. The predominance of the relatively uncommon V region subgroup isotype kappa III among the light chains of human monoclonal (IgM kappa) anti-IgG antibodies, i.e., rheumatoid factors, was further evidenced through sequence and serological analyses of 10 such autoantibodies isolated from IgManti-IgG cold-insoluble immune complexes (mixed cryoglobulins). The N-terminal sequence and V region determinants of all 10 kappa-chains were characteristic for kappa III proteins and virtually identical to that of a prototype kappa III light chain. Similar sequence and antigenic identity were found for kappa-chains isolated from three IgM kappa autoantibodies that formed cold-insoluble immune complexes with LDL.